A model of human B cell activation, proliferation and terminal differentiation was established in which the spectrum of specific and non-specific activation signals as well as various growth and differentiation factors were precisely delineated. Immunoregulatory T cell and monocyte subsets and the diverse mechanisms of their modulation of B cell responses were delineated. Radiation sensitivity and precursor frequency studies of immunoregulatory T cells as well as limiting dilution analyses of antigen-specific B cells were performed. The phenomenon of high antigen concentration blockade of B cell differentiation in the face of normal B and T cell proliferation was described. The relationship between the primary activation of B cells by antigen and the subsequent antigen-independent driving of these cells towards terminal differentiation by non-specific soluble factors was studied. The genetic restriction of monocyte-T cell interactions in the induction of T cell dependent B cell responses as well as the role of Ia and certain cell surface activation molecules in the antigen-induced activation of B cells were described. Selective elimination of antigen-reactive B cell clones by antigen-toxin conjugates was demonstrated. The complex mechanisms of modulation of human B cell responses by corticosteroids and cytotoxic agents were defined.